Multiple previous studies outline the epidemiology and clinical course of invasive candidiasis in the NICU, but there have been limited studies of candidal UTI in the absence of extra-renal disease as detected by routine investigations. This report describes 30 such cases presenting to 13 Canadian NICUs over a 30-month period, many in term or near-term infants with major congenital abnormalities of the heart or kidneys. In addition our results suggest a lack of distinguishing clinical or laboratory features at diagnosis, a high rate of abnormalities on renal ultrasonography (>50%), and a significant proportion (one third) of the total mortality related to Candida infection.
Our finding of candidal UTI in term infants with congenital anomalies differs from two previously published studies of candidal UTIs in NICUs. Philips et al used an identical definition for candidal UTI to the current study but only enrolled infants 7 days of age or older (n = 25) . The second study by Bryant et al enrolled infants from birth (n = 41) but accepted any growth of Candida from a catheterized urine as being indicative of a UTI . These previous studies described candidal UTIs mainly in very low birth weight infants (median gestational age 26 weeks  and 27 weeks  versus 35 weeks in the current study). This discrepancy is likely due to our exclusion of infants who had candidemia on the day of diagnosis of candidal UTI. In the cohort of 66 infants with systemic candidiasis that were part of our larger study who met the first inclusion criteria but are not included in the current report, 8 infants had both blood and urine cultures positive for Candida and their median gestational age was 25.5 weeks (unpublished data), consistent with these previously published studies. Differences in NICU populations between the studies may also be a factor with the current multicenter study including a higher proportion of term infants with congenital heart disease than many studies of single NICUs. Although there are no previous studies looking at candidal UTI in term or near-term infants in NICU, a study that looked at invasive candidiasis in infants with a birth weight over 2500 grams described 13 of 17 infants (76%) with serious congenital anomalies . This pattern fits with the current study where two-thirds of the infants were born after 29 weeks gestation and over half had serious congenital anomalies. In a study from the United Kingdom of infants with fungal infections and a birthweight < 1500 grams, 26 of 94 cases had funguria with 6 having isolated funguria . The species of Candida were comparable in all NICU candidal UTI studies to date (Table 2).
On renal ultrasonography, parenchymal changes predominated in the current study, suggesting the possibility of unrecognized hematogenous spread of Candida in infants who are suspected to have candidal infection limited to the urinary tract. Ascending infection would be expected to result in isolated pelvicalyceal disease, with only 3 of the 15 abnormal renal ultrasounds fitting this pattern. However, the terminology for renal ultrasonography reporting in neonates is not uniform. Renal fungal balls or abscesses were suspected in 35%  and 42%  of the 55 infants with renal imaging or autopsy diagnoses in the previous studies. In the current study, only 12% of the 26 infants with renal imaging had a fungal ball mentioned in the report, but many had changes that appeared to be consistent with those reported as fungal balls in a previous study . Renal fungal balls can be confused with fibrin, blood clots, necrotic papillae, nephrocalcinosis, or tumors on renal ultrasonography  so that the interpretation may be influenced by the information provided to the radiologist about the possibility of candidal infection. In one study, about half of the suspected fungal balls were apparent only on follow-up ultrasounds  which were not routinely performed in the current study.
Although surgical intervention for renal fungal disease in the collecting system has been described in numerous case reports , it was not required for infants with fungal balls in our study. For the 66 infants with candidal UTI described in the two previous case series [3, 4]22 infants had suspected fungal balls with 2 having partial obstruction but surgery was required for only one infant with a renal abscess . In another recent study of 9 infants with suspected renal fungal balls, surgical management was not required . This suggests that medical management can be anticipated to be successful in the majority of cases, even in the presence of documented fungal balls on imaging, unless there is concomitant total obstruction.
The need for, choice and duration of antifungal treatment for candidal UTI in the absence of extra-renal disease has not been studied and there are no widely-accepted guidelines, explaining the marked variation in therapy in the current study. Two of the 3 deaths that were thought to be related to candidal infection were a result of dissemination of disease, indicating that cases with "apparent isolated candiduria" may later disseminate or may have undetected foci of infection at non-renal distant sites. The significant rate of extra-renal dissemination (13.3%) supports the use of systemic antifungal therapy when candiduria occurs with a significant colony count in the NICU.
Most infants with candidal UTI in previous reports were successfully treated with AMP or FCZ, typically given for a minimum of 7 days after urine cultures became sterile . Much longer courses have often been given if changes are noted on renal ultrasonography, but it appears that there is no need to document resolution of these changes prior to stopping therapy  There were only 2 cases of suspected treatment failure in the current study where death was attributable to candidal infection despite 7 or more days of appropriate therapy, both in infants with extra-renal dissemination (Table 1). There were no recurrences of candiduria, suggesting that any of the multiple regimes used by clinicians for candidal UTI are likely to be successful if extra-renal invasive candidal infection has been excluded. Two of the three cases of candidemia occurred after long courses of antifungals, suggesting that extra-renal candidal infection should be sought even in infants on treatment with a slow response to therapy. The role of parenteral prophylactic antifungals for candiduria could not be addressed in the current study as they were not used in any of the NICUs.
The primary limitation in drawing conclusion from this study is that although the patients were enrolled prospectively, investigations for dissemination were at the discretion of the attending physician. This resulted in not all patients being consistently evaluated for meningitis, retinitis, renal parenchymal disease, recurrent candiduria, or even candidemia. However, we recognize that false-negative blood and CSF cultures occur frequently in neonatal candidasis so associated morbidity is not always recognized even when infants are fully evaluated for disseminated disease. Nonetheless, even though it is widely accepted that all infants with candidemia should be investigated for end-organ damage , the need for full investigation of infants with candiduria in the absence of candidemia is less clear from the previous literature. The role of fundoscopy in infants with candiduria alone is not clear although a study has shown a higher incidence of candidial retinitis with candidaemia of greater gestational age , suggesting that fundoscopy is indicated even in term infants with extra-renal candidiasis.
Further limitations are that it would have been ideal to have all renal ultrasounds interpreted by a single radiologist, and that changes in management of infants will have occurred since this study was performed. For example, fewer infants would be exposed to post-natal corticosteroids and echindocandins are now used as antifungal therapy in some centers.
One of the limitations of all studies to date is that definitions devised for the diagnosis of bacterial UTIs have been extrapolated to fungal UTIs, without validation of these definitions in any age group . There are no standard definitions for colony counts defining UTIs in children with indwelling bladder catheters  which would include a small number of infants in the current study. The fact that over half of the renal ultrasounds in our study demonstrated abnormalities consistent with fungal infection of the renal parenchyma or collecting system suggests that the specificity of the definitions used is reasonable. It is however possible that clinically significant fungal UTIs can occur at lower colony counts than those applied in this study, as has been described in infants with suspected fungal balls . In addition, infants with fungal UTI may have been missed if only a bag urine had been submitted or if antifungals had been started prior to obtaining the urine specimen.